Molecular Pharmacology, Physiology, and Structure of the P2Y Receptors
Molecular Pharmacology, Physiology, and Structure of the P2Y Receptors
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DOI：
10.1016/b978-0-12-385526-8.00012-6
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Harden, T. Kendall
中科院分区：
文献类型：
--
作者：
von Kuegelgen, Ivar;Harden, T. Kendall
P2 Y受体是一组广泛表达的八种核苷酸激活的G蛋白偶联受体（GPCR）。P2 Y（1）（ADP）、P2 Y（2）（ATP/UTP）、P2 Y（4）（UTP）、P2 Y（6）（UDP）和P2 Y（11）（ATP）受体激活G（q），因此强烈促进肌醇脂质信号传导反应。P2 Y（12）（ADP）、P2 Y（13）（ADP）和P2 Y（14）（UDP/UDP-葡萄糖）受体激活G（i），导致腺苷酸环化酶的抑制和G β γ介导的一系列效应蛋白的激活，包括磷酸肌醇3-激酶-β、内向整流K+（GIRK）通道、磷脂酶C-β 2和-β 3以及G蛋白受体激酶2和3。在这些受体活化的下游发生广泛的生理反应，范围从上皮细胞的Cl-分泌到血小板的聚集到神经传递。P2 Y受体的有用的结构模型已经从广泛的遗传分析与基于视紫红质和其他几种GPCR获得的三维结构的分子建模相结合发展而来。已经合成了大多数P2 Y受体的选择性配体，其中最显著的成功是用ADP活化的P2 Y1和P2 Y12受体的高选择性激动剂和拮抗剂分子获得的。广泛使用的处方药氯吡格雷导致血小板P2 Y12受体的不可逆阻断，是靶向P2 Y受体的最重要的治疗剂。
The P2Y receptors are a widely expressed group of eight nucleotide-activated G protein-coupled receptors (GPCRs). The P2Y(1)(ADP), P2Y(2)(ATP/UTP), P2Y(4)(UTP), P2Y(6)(UDP), and P2Y(11)(ATP) receptors activate G(q) and therefore robustly promote inositol lipid signaling responses. The P2Y(12)(ADP), P2Y(13)(ADP), and P2Y(14)(UDP/UDP-glucose) receptors activate G(i) leading to inhibition of adenylyl cyclase and to G beta gamma-mediated activation of a range of effector proteins including phosphoinositide 3-kinase-beta, inward rectifying K+ (GIRK) channels, phospholipase C-beta 2 and -beta 3, and G protein-receptor kinases 2 and 3. A broad range of physiological responses occur downstream of activation of these receptors ranging from Cl- secretion by epithelia to aggregation of platelets to neurotransmission. Useful structural models of the P2Y receptors have evolved from extensive genetic analyses coupled with molecular modeling based on three-dimensional structures obtained for rhodopsin and several other GPCRs. Selective ligands have been synthesized for most of the P2Y receptors with the most prominent successes attained with highly selective agonist and antagonist molecules for the ADP-activated P2Y1 and P2Y12 receptors. The widely prescribed drug, clopidogrel, which results in irreversible blockade of the platelet P2Y12 receptor, is the most important therapeutic agent that targets a P2Y receptor.